The objective of this program project is to exploit the biochemistry and physiology of tumor tissues in order to increase their vulnerability to radiation and, in some cases, chemotherapy. The uniqueness of this program is threefold: 1. an outstanding group of scientists with expertise in radiation oncology, biology, metabolism and imaging techniques has been assembled; 2. these researchers have developed state-of-the-art technology to measure steady state concentrations of oxygen or metabolites as indicators of metabolic status; 3. the group's extensive knowledge of metabolism combined with these improved detection devices will bring about an impact on patient treatment. The clinician will be given additional predictive information for the first time. Instead of relying only on tumor size and pathology, the clinician will have information on tumor oxygenation and metabolic state to determine treatment. Increased reliability will result from the use of several independent techniques to assess tumor state. These techniques include the non-invasive identification of tumor oxygenation via near-infrared spectroscopy (NIR) and redox scanning (Project 4), the measurement of oxygen consumption and the binding of drugs to hypoxic tumor tissue (Project 3), and the use of phosphorescence quenching to monitor tumor oxygenation (Project 2). The reliability of these techniques will be cross-tested in similar tumor systems under various conditions of biochemical modulation (Project 1). Information on the metabolic state obtained by the various procedures will be used to determine the proper time to treat the tumor with radiation. These extremely accurate measurements of the metabolic state will also provide information on the group's ability to alter tumor state in vivo and its potential impact in the clinical setting, i.e., treatment design. Clinical applications will be enhanced by the presence of clinical radiologists and radiation oncologists int he research group. In addition, metabolites, antimetabolites and hormones will be employed to increase tumor radiosensitivity. Preliminary results show that innocuous agents (glucose, phosphate, carbogen, nicotinamide) can be used with insulin to improve the radiation response in vitro and in vivo. A number of established tumors with well-characterized and differing radiation responses and cellular make-up will be used to refine the group's techniques, test hypotheses, and develop protocols. The group is confident that this integration of state-of-the-art technology, combined with its metabolic expertise, will lead to improved therapy.